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Disruptions to the oxygen and blood supply in the perinatal brain affect the cerebral microenvironment and may affect microglial activation, excitotoxicity, and oxidative stress. Microglia are significantly associated with axonal damage and myelinating oligodendrocytes, which are major pathological components of WMI. However, the effects of H\u2010I injury on microglial functions and underlying transformation mechanisms remain poorly understood. The historical perception that these cells are major risk factors for ischemic stroke has been questioned due to our improved understanding of the diversity of microglial phenotypes and their alterable functions, which exacerbate or attenuate injuries in different regions in response to environmental instability. Unfortunately, although therapeutic hypothermia is an efficient treatment, death and disability remain the prognosis for a large proportion of neonates with H\u2010I injury. Hence, novel neuroprotective therapies to treat WMI following H\u2010I injury are urgently needed. Here, we review microglial mechanisms that might occur in the developing brain due to neonatal H\u2010I injury and discuss whether microglia function as a double\u2010edged sword in WMI. Then, we emphasize microglial heterogeneity, notably at the single\u2010cell level, and sex\u2010specific effects on the etiology of neurological diseases. Finally, we discuss current knowledge of strategies aiming to improve microglia modulation and remyelination following neonatal H\u2010I injury. Overall, microglia\u2010targeted therapy might provide novel and valuable insights into the treatment of neonatal H\u2010I insult.<\/jats:p>","DOI":"10.1002\/jnr.24761","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T02:21:32Z","timestamp":1610504492000},"page":"991-1008","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["White matter injury in the neonatal hypoxic\u2010ischemic brain and potential therapies targeting microglia"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-560X","authenticated-orcid":false,"given":"Rongjiao","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department 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